Effects of the beta-amyloid and carboxyl-terminal fragment of Alzheimer's amyloid precursor protein on the production of the tumor necrosis factor-alpha and matrix metalloproteinase-9 by human monocytic THP-1

To explore the direct role of beta -amyloid (A beta) and carboxyl-terminal fragments of amyloid precursor protein in the inflammatory processes possib ly linked to neurodegeneration associated with Alzheimer's disease, the eff ects of the 105-amino acid carboxyl-terminal fragment (CT105) of amyloid pr ecursor protein on the production of tumor necrosis factor-cu (TNF-alpha) a nd matrix metalloproteinase.9 (MMP-9) were examined in a human monocytic TH P-1 cell line and compared with that of A beta. CT105 elicited a marked inc rease in TMF-alpha and MMP-9 production in the presence of interferon-gamma in a dose- and time-dependent manner. Similar patterns were obtained with A beta despite its low magnitude of induction. Autocrine TNF-alpha is likel y to be a main mediator of the induction of MMP-9 because the neutralizing antibody to TNF-alpha inhibits MMP-9 production. Genistein, a specific inhi bitor of tyrosine kinase, dramatically diminished both TNF-alpha secretion and subsequent MMP-9 release in response to CT105 or A beta. Furthermore, P D98059 and SB202190, specific inhibitors of ERK or p38 MAPK respectively, e fficiently suppressed CT105-induced effects whereas only PD98059 was effect ive at reducing A beta -induced effects. Our results suggest that CT105 in combination withinterferon-gamma might serve as a more potent activator tha n A beta in triggering inflammatory processes and that both tyrosine kinase and MAPK signaling pathways may represent potential therapeutic targets fo r the control of Alzheimer's disease progression.